(a) Field of the Invention
The present invention relates to thiazole-based compounds represented by following Chemical Formula 1, and T-type calcium channel inhibitors containing the compound. The T-type calcium channel inhibitors according to the present invention are useful as a treating agent of diseases associated with over-expression of T-type calcium channel.

(b) Description of the Related Art
T-type calcium channel is a kind of voltage-dependent calcium channels, which plays an important role in regulating intracellular calcium level at depolarization. As coding genes for the voltage-dependent calcium channels, ten (10) genes have been found, which may be classified into two (2) families, a high voltage activated (HVA) family and a low voltage activated (LVA) family, according to the intensity of the activating voltage. The voltage-dependent calcium channels may be classified into three (3) families, L-type channels (Cav1), P/Q-type and N-type (nervous unit) channels (Cav2), and T-type channels, wherein the L-type channels, and P/Q-type and N-type channels belong to the high voltage activated family, and the T-type channels belong to the low voltage activated family (Ertel et al., 2000).
T-type calcium channel is characterized by low-voltage activated calcium current, rapid activation and slow inactivation. Up to date, as coding genes for the T-type calcium channel, three (3) genes have been identified, and named as α1G (Cav3.1), α1H (Cav3.2), and α1I (Cav3.3), respectively (Cribbs et al., 1998; Perez-Reyes et al., 1998; Klugbauer et al., 1999; Lee et al., 1999; Monteil et al., 2000). The T-type calcium channels may be expressed in whole body, such as a nervous tissue, heart, kidney, smooth muscle, and endocrine organ. The T-type calcium channels have been found to have the functions to regulate bursting firing of nervous cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), heart pacemaker activity (Zhou, Z et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of hormone aldosterone (Rossier, M. F. et al., Endocrinology 1996, 137, 4817-4826) and fertilization (Arnoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009). Recently, it has been revealed that the T-type calcium channels are also associated with pain signaling (Ikeda, H. et al., Science, 2003, 299, 1237-1240).
The relationship between the expression of the T-type calcium channel and various diseases has been found. The expression of the T-type calcium channel in brain is found to be associated with nociception and repetitive low threshold firing. Especially, a recent study reported a direct relationship between the expression of the T-type calcium channel and pain using a knock-out mouse wherein T-type calcium channel is deleted (Bourinet E. et al., EMBO, 2005, 24, 315-324; Shin, H. S. et al., Science, 2003, 302, 117-119). In addition, the T-type calcium channel is associated with epilepsy. Absent seizure, which is a type of epilepsy, is caused by over-activation of T-type calcium channel in brain (Tsakiridou E et al., J. Neurosci. 1995, 15, 3110-3117). Ethosuccimide is an inhibitor against T-type calcium channel, and has been used in treatment of absence seizure. T-type calcium channel is commonly expressed in heart and smooth muscle, and thus, the inhibitors thereof can be also useful in treatment of hypertension, angina pectoris, and arrhythmia. Recently, it has been found that the T-type calcium channel is associated with the invasion and metathesis of cancer cells, and thus, the inhibitors thereof may be useful as anticancer drugs (Petty, H. R. et al., US 20060003020A1; McCalmont, W. F. et al, Bioorg. Med. Chem. Lett. 2004, 14, 3691-3695).
The exemplary inhibitor against the T-type calcium channel is miberefradil (Posicor®) developed by Roche. Mibefradil, which is a non-dihydropyridine calcium channel inhibitor, obtained FDA approval as a treating drug against hypertension and angina pectoris in 1997. However, Mibefradil has been voluntarily removed since 1999 because of its side effect caused by drug-drug interaction by CYP 3A4 enzyme inhibition.
Therefore, efficient T-type calcium channel inhibitors have not been developed yet. In view of the effects of T-type calcium channel on nerve, pain, epilepsy, hypertension, angina pectoris, heart muscle diseases, blood vessels, cancer metathesis, it has been required to develop efficient T-type calcium channel inhibitors capable of preventing and treating various T-type calcium channel associated diseases by inhibiting the over-expression and over-activation of T-type calcium channel.